1. Field of the Invention
The present invention relates to the field of nutritional therapy. Specifically, the present invention provides novel compositions containing the necessary amino acids which, when administered to a mammal, are capable of decreasing the catabolic breakdown of body tissue. Such breakdown can be associated with acute catabolic states or injury, medical therapies such as the use of anti-inflammatory agents, and acute exercise.
2. Description of the Background Art
The breakdown of body tissue can be associated with a variety of catabolic conditions as well as a side effect of various medical treatments. Catabolic breakdown of body tissue occurs in patients during semistarvation (Pozefsky et al., J. Clin. Invest. 57:444-449 (1976)), prolonged fasting (Felig et al., J. Clin. Invest. 48:584-594 (1969)), acute exercise (Felig et al., J. Clin. Invest. 50:2703-2714 (1971)), injury (Aulick et al., Surgery 85:560-565 (1982)), protein feeding (Abumrad et al., Metabolism 31:463-470 (1982)), infection (Fong et al., J. Clin Invest. 85:1896-1904 (1990)), trauma (Brooks et al., J. Surg. Res. 40:395-405 (1986)), and steroidal therapy especially glucocorticoids (Kaplan S. A. and Shimizu, C. S.; Endocrinology 72:267-272 (1963); Ryan W. and Carver, M., Proc. Exp. Biol. Med. 114:816-819 (1963); Muhlbacher F. et al., Am. J. Physiol. 247:E75-E83 (1984)).
As a result of each of the above, patients experience a marked decrease in tissue mass due to catabolic breakdown. The mechanism leading to the tissue breakdown is unclear; however, it has been postulated that tissue breakdown is but one of the bodily defenses which is mounted against injury, the effect being to increase the inter- and intracellular supply of amino acids. Such amino acids supply the necessary elements for other metabolic activity (such as replication and function of immune and other cells and wound repair) as well as supplying energy.
In general, patients suffering from a severe acute catabolic state can require some type of nutritional therapy. The nutritional requirements of these patients are met through the administration of either an enteral or parenteral diet. Enteral diets are usually administered using small-bore tubing which is placed through the nose into the gastric, or duodenal regions, or through surgical implantation as in, for example, gastrostomy, or jejunostomy.
Parenteral diets are usually administered intravenously (i.v.). These i.v. fluids are sterile solutions composed of simple chemicals such as, for example, sugars, amino acids, and electrolytes, which can be easily assimilated.
The term "total parenteral nutrition" (TPN) is used to describe formulas for use in patients who derive their dietary requirements intravenously. Total parenteral formulas, unlike enteral formulas, do not normally contain the non-essential amino acid glutamine (GLN). The absence of GLN from parenteral formulas is due, in part, to the long standing belief that GLN belongs to those non-essential amino acids which do not need to be administered in appreciable amounts to patients undergoing TPN. Additionally there is concern with breakdown of GLN because of long-term instability at room temperature and especially during heat sterilization which results in generation of ammonia and pyroglutamic acid. A lesser concern has been the generation of glutamic acid from GLN because of the potential toxicity of glutamic acid as a neurotransmitter. This is not a clinically important problem, for glutamic acid is found in many commercially available intravenous amino acid formulas.
Glutamine has been included in several enteral formulations. These include Vivonex, Immun-Aid or Alitraq (see Table 5). In general, these formulations have been generated by adding free glutamine to a high biological protein source. No parenteral nutrient solutions containing glutamine are commercially available; experimental solutions have been constructed by adding dipeptides of L-glutamine to standard formulas (Stehle et al., Lancet 1:231-233 (1989), Hammarqvist et al., Ann. Surg. 209:455-461 (1989)). However, as discussed later, these formulations have not been designed to reflect the various amino acids released during catabolism.
Until now, enteral and parenteral diets have been formulated to provide the energy and amino acids necessary to achieve positive nitrogen balance in normal individuals. However, the various formulations available are generally based on the dietary requirements of a normal individual and increase or only slightly after these requirements for the commonly seen acute catabolic states. As such, current nutritional therapy does not eliminate tissue catabolism (Warnold et al., Ann. Surg. 208:143-149 (1988); Iapichino et al., Crit. Care Med. 18:1367-1373 (1990)).